Dataset Information

Potential value of urine lateral-flow lipoarabinomannan (LAM) test for diagnosing tuberculosis among severely acute malnourished children.

ABSTRACT:

Background

Tuberculosis (TB) is a serious co-morbidity among children with severe acute malnutrition (SAM) and TB diagnosis remains particularly challenging in the very young. We explored whether, in a low HIV-prevalence setting, the detection of mycobacterial lipoarabinomannan (LAM) antigen in urine may assist TB diagnosis in SAM children, a pediatric population currently not included in LAM-testing recommendations. To that end, we assessed LAM test-positivity among SAM children with and without signs or symptoms of TB.

Methods

A cross-sectional assessment (February 2016-August 2017) included children <5 years with SAM from an Intensive-Therapeutic-Feeding-Centre in Madaoua, Niger. Group 1: children with signs or symptoms suggestive of TB. Group 2: children without any sign or symptom of TB. Urine-specimens were subjected to DetermineTM TB-LAM lateral-flow-test (using a 4-grade intensity scale for positives). LAM-results were used for study purposes and not for patient management. Programmatic TB-diagnosis was primarily based on patients' clinical symptoms and TB contact history with no systematic access to X-ray or microbiological reference testing.

Results

102 (Group 1) and 100 children (Group 2) were included (median age 18 months, 59.4% male, 1.0% HIV-positive). In Group 1, 22 (21.6%) children were started on TB-treatment (probable TB) and none of the children in Group 2. LAM-positivity was 52.0% (53/102) and 37.0% (37/100) in Group 1 and 2, respectively. Low-intensity (Grade 1) LAM test-positivity was similarly high in both Groups (37.3% and 36.0%, respectively), while Grade 2 or 3-positives were mainly detected in Group 1 (Group 1: 14.7%, Group 2: 1.0%, p<0.001). When considering only Grades >1 as positive, LAM-testing detected 22.7% (95%CI: 7.8, 45.4) among probable TB cases, while 99% (95%CI: 94.6, 99.9) of unlikely TB cases (Group 2) tested negative.

Conclusion

These findings suggest the potential utility of LAM urine testing in HIV-negative children with SAM. Determine LAM-positivity with Grades >1 may identify HIV-negative SAM children that are eligible for rapid TB-treatment initiation, though low-intensity (Grade 1) LAM-positive results may not be helpful in this way. Further studies in this specific pediatric population are warranted, including evaluations of new generation LAM tests.

SUBMITTER: Schramm B

PROVIDER: S-EPMC8099085 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTuberculosis (TB) is a global burden, and this is likely to remain the case due to a lack of adequate and accurate point-of-care diagnostic tests. Obtaining good-quality sputum from the bottom of the respiratory tract of children is challenging. Lipoarabinomannan (LAM) is a specific component of the mycobacterial cell envelope that is excreted in the urine of people with active TB. This study aimed to assess the performance of different types of urine-based LAM antigen tests for the diagnosis of TB in children.MethodsRelevant databases were searched for studies that used urine-based LAM tests to diagnose TB in children. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Tool. Pooled sensitivity and specificity were calculated using the random-effect model in STATA Version 16.0. Moreover, subgroup analysis was undertaken to hinder the heterogeneity of the studies.ResultsEleven articles were included in the final systematic review and meta-analysis. The pooled sensitivity and specificity of the Mycobacterium tuberculosis enzyme-linked immunosorbent assay (MTB-LAM-ELISA), Alere Determine TB LAM Ag (Alere LAM) test and the Fujifilm SILVAMP TB LAM (Fuji LAM) test in children aged <15 years with TB were 16.0% [95% confidence interval (CI) 10.25-42.25] and 95.61% (95% CI 93.74-97.74); 45.90% (95% CI 40.40-51.40) and 80.42% (95% CI 69.39-91.46); and 52.32% (95% CI 35.03-69.62) and 89.37% (95% CI 82.88-95.86), respectively. Subgroup analysis revealed that the pooled sensitivity and specificity of MTB-LAM-ELISA, Alere LAM test and Fuji LAM test were 33.5% (95% CI 34.86-100) and 95.83% (95% CI 91.50-100); 46.59% (95% CI 32.98-60.19) and 76.45% (95% CI 57.07-95.82); and 57.89% (95% CI 48.44-67.35%) and 87.66% (95% CI 75.29-100), respectively, in human immunodeficiency virus (HIV)-positive children; and 3.35% (95% CI 1.61-8.31) and 96.0% (95% CI 93.88-98.11); 32.33% (95% CI 7.63-57.03) and 79.07% (95% CI 62.62-95.51); and 50.95% (95% CI 27.45-74.45) and 89.47% (95% CI 84.72-94.22), respectively, in HIV-negative children.ConclusionThe Fuji LAM and Alere LAM tests may be useful for the diagnosis of TB in children in conjunction with other more sensitive and specific tests, although a prospective study in relevant clinical settings is needed to evaluate this. There is a need for more evidence-based data on the use of these rapid diagnostic tools to diagnose TB in children independent of HIV status.

Project description:Background: Since 2015, the World Health Organization (WHO) has recommended a commercially available lateral-flow urine LAM test (Alere-LAM) to assist in the diagnosis of tuberculosis (TB) in severely ill people living with HIV (PLHIV). The test can rapidly detect TB in severely ill PLHIV and can identify PLHIV most at-risk of death, leading to mortality reductions. However, its uptake in countries with high burdens of TB and HIV has been slow. To assess the current use landscape and identify barriers to the adoption of Alere-LAM, we conducted a questionnaire-based study in 31 high TB and HIV/AIDS burden countries. Methods: Between November 2018 and December 2019, we collected responses to a semi-structured questionnaire that had been emailed to staff and affiliates of National TB Programs or HIV/AIDS Programs, Ministries of Health, and TB or HIV institutes of 31 high TB/HIV burden countries. Questions concerned country policies, adoption, and current use of Alere-LAM testing, as well as testing algorithms and barriers preventing Alere-LAM uptake. Results: We received questionnaire responses from 24 out of 31 (77%) high TB/HIV burden countries. Of these 24 countries, 11 (46%) had adopted Alere-LAM policies, with only five (21%) countries currently using Alere-LAM testing. Testing algorithms were generally aligned with WHO recommendations. Fifteen countries (63%) said they were planning to implement Alere-LAM testing in the near future. The most commonly cited constraint to adoption and implementation was budget limitations. Additional barriers to Alere-LAM implementation included lack of country-specific data and piloting, administrative hurdles such as regulatory agency approval, lack of coordination between National TB and HIV programs, and small perceived patient population. Conclusion: Responses to our questionnaire demonstrate the persistent gap between country-level policy and real-world use of Alere-LAM, as well as specific barriers that must be addressed to scale-up testing in PLHIV.

Project description:BACKGROUND:Tuberculosis (TB) is the leading cause of death among HIV-positive patients. We assessed the cost-effectiveness of including lateral-flow urine lipoarabinomannan (LF-LAM) in TB diagnostic algorithms for severely ill or immunosuppressed HIV-positive patients with symptoms of TB in Kenya. METHODS:From a decision-analysis tree, ten diagnostic algorithms were elaborated and compared. All algorithms included clinical exam. The costs of each algorithm were calculated using a 'micro-costing' method. The efficacy was estimated through a prospective study that included severely ill or immunosuppressed (CD4<200cells/μL) HIV-positive adults with symptoms of TB. The cost-effectiveness analysis was performed using the disability-adjusted life year (DALY) averted as effectiveness outcome. A 4% discount rate was applied. RESULTS:The algorithm that added LF-LAM alone to the clinical exam lead to the least average cost per TB case detected (€47) and was the most cost-effective with a cost/DALY averted of €4.6. The algorithms including LF-LAM, microscopy and X-ray, and LF-LAM and Xpert in sputum, detected a high number of TB cases with a cost/DALY averted of €6.1 for each of them. In the comparisons of the algorithms two by two, using LF-LAM instead of microscopy (clinic&LAM vs clinic&microscopy) and using LF-LAM along with GeneXpert in sputum instead of GeneXpert in urine along with GeneXpert in sputum, (clinic&LAM&Xpert_sputum vs clinic&Xpert_sputum&Xpert_urine) led to the highest increase in the cost-effectiveness ratios (ICERs): €-7.2 and €-12.6 respectively. In these two comparisons, using LF-LAM increased the number of TB patients detected while reducing costs. Adding LF-LAM to smear microscopy alone or to smear microscopy and Xray led to the highest increase in the additional number of TB cases detected (31 and 25 respectively) with an incremental efficiency estimated at 134 and 344 DALYs respectively. The ICERs were €22.0 and €8.6 respectively. CONCLUSION:Including LF-LAM in TB diagnostic algorithms is cost-effective for severely ill or immunosuppressed HIV-positive patients.

Project description:BackgroundThe use of the point-of-care lateral flow lipoarabinomannan (LF-LAM) test may expedite tuberculosis (TB) diagnosis in HIV-positive patients. However, the test's clinical utility is poorly defined outside sub-Saharan Africa.MethodsThe study enrolled consecutive HIV-positive adults at a tertiary referral hospital in Yangon, Myanmar. On enrolment, patients had a LF-LAM test performed according to the manufacturer's instructions. Clinicians managing the patients were unaware of the LF-LAM result, which was correlated with the patient's clinical course over the ensuing 6 months.ResultsThe study enrolled 54 inpatients and 463 outpatients between July 1 and December 31, 2015. On enrolment, the patients' median (interquartile range) CD4 T-cell count was 270 (128-443) cells/mm3. The baseline LF-LAM test was positive in 201/517 (39%). TB was confirmed microbiologically during follow-up in 54/517 (10%), with rifampicin resistance present in 8/54 (15%). In the study's resource-limited setting, extrapulmonary testing for TB was not possible, but after 6 months, 97/201 (48%) with a positive LF-LAM test on enrolment had neither died, required hospitalisation, received a TB diagnosis or received empirical anti-TB therapy, suggesting a high rate of false-positive results. Of the 97 false-positive tests, 89 (92%) were grade 1 positive, suggesting poor test specificity using this cut-off. Only 21/517 (4%) patients were inpatients with TB symptoms and a CD4 T-cell count of < 100 cells/mm3. Five (24%) of these 21 died, three of whom had a positive LF-LAM test on enrolment. However, all three received anti-TB therapy before death - two after diagnosis with Xpert MTB/RIF testing, while the other received empirical treatment. It is unlikely that knowledge of the baseline LF-LAM result would have averted any of the study's other 11 deaths; eight had a negative test, and of the three patients with a positive test, two received anti-TB therapy before death, while one died from laboratory-confirmed cryptococcal meningitis. The test was no better than a simple, clinical history excluding TB during follow-up (negative predictive value (95% confidence interval): 94% (91-97) vs. 94% (91-96)).ConclusionsThe LF-LAM test had limited clinical utility in the management of HIV-positive patients in this Asian referral hospital setting.

Project description:The commercially available urine LAM strip test, a point-of-care tuberculosis (TB) assay, requires evaluation in a primary care setting where it is most needed. There is currently inadequate data to guide implementation in TB and HIV-endemic settings.Adult HIV-infected outpatients with suspected pulmonary TB able to self-expectorate sputum from four primary clinics in South Africa, Zambia and Tanzania underwent diagnostic evaluation [sputum smear microscopy, Xpert-MTB/RIF, and culture (reference standard)] as part of a prospective parent study. Urine LAM testing (grade-2 cut-point) was performed on archived samples. Performance characteristics of LAM alone or in combination with sputum-based diagnostics were evaluated. Potential impact on 2 and 6-month morbidity (TBscore), patient dropout rates, and prognosis (death/ loss to follow-up) were evaluated.Among 583 participants with suspected TB that were HIV-infected or refused testing, the overall LAM sensitivity (95 % CI; n/N) and in the CD4 ? 100 cells/mm(3) sub-group was 22.7 % (16.6-28.7; 41/181) and 30.4 % (17.1-43.7; 14/46), respectively. Overall specificity was 93.0 % (90.5-95.6; 361/388). Amongst culture-positive TB cases, adjunctive LAM testing did not improve the sensitivity of either sputum Xpert-MTB/RIF [78.2 % (69.8-86.7; 72/92) versus 76.1 % (67.4-84.8; 70/92), p = 0.7] or smear-microscopy [56.2 % (45.9-66.5; 50/89) versus 43.8 % (33.5-54.1; 39/89), p = 0.1). Clinic-based LAM, as an adjunct to either smear microscopy or Xpert MTB/RIF same-day testing, would neither have decreased patient dropout, nor increased same-day treatment initiation in this clinical setting where same-day chest radiography was available. LAM positivity was associated with 6-month lost-to-follow-up/death (AOR 4.4; p = 0.002) but not TBscore (at baseline or change in TBscore 2-months post-treatment) (p = 0.17).In African HIV-TB co-infected outpatients able to self-expectorate sputum LAM had limited sensitivity even at low CD4 counts, and offered no significant incremental diagnostic yield over Xpert-MTB/RIF or smear microscopy. In primary care clinics with chest radiography and where empiric TB treatment is common, LAM seems unlikely to improve rates of same-day treatment initiation and patient dropout, however, the ability of LAM to identify patients at high risk of death or lost-to-follow-up may offer important prognostic value.